The overall goal of this HIV Vaccine Research and Development grant competing renewal application is to study the mechanisms and feasibility of using HSV recombinants expressing AIDS viral proteins to induce protective immune responses against SIV or HIV. This research program will focus on the design, characterization, and optimization of HSV recombinant vectors expressing SIV and HIV proteins. A novel feature of this program is the recent observation that HSV vector immunization induced cellular memory responses and reduction of viral load following intravenous challenge by pathogenic SIV in rhesus macaques. Thus, the Program will focus on the novel properties of the HSV vectors and the types of memory immune responses that they induce in nonhuman primates. The individual projects and cores in this current application are summarized as follows: David Knipe. Development of HSV Vectors as AIDS Vaccines. This project will conduct studies to test several hypotheses regarding the basic properties of herpes simplex virus vectors that have multiple immediate early genes mutated and to optimize the expression and immunogenicity of HIV and SIV proteins. Amitinder Kaur and Ron Desrosiers Immune Responses and Protection in Macaques Immunized with HSV Vaccine Vectors. This project will examine the nature of immunologic memory induced by different recombinant HSV immunization protocols and determine how it relates to protection against SIV infection of rhesus macaques. Administrative Core. The Administrative Core will 1) provide Program leadership for integration of the projects and cores and in the decisions about the use of recombinant HSV vectors in primate studies and the selection of HSV recombinants for clinical development and 2) provide administrative support for the conduct of the research proposed in this application. Immunology Core. The Immunology Core will conduct immunological assays on cells and serum from mice immunized in Project 1 and from rhesus macaques. Cellular assays will include ELISPOT, intracellular cytokine staining, and 10-color flow cytometry. Antibody assays will include ELISA and neutralization assays for SIV and HSV.